It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored “Heart Study of Hemochromatosis.” They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p <0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation.
The association of cardiac arrhythmia with hereditary hemochromatosis (HH) has been well documented. However, most of published data have described cases of cardiac arrhythmia in the presence of heart failure due to iron overload. Thus, it is difficult to determine whether the cardiac arrhythmia detected in subjects with HH is directly linked to systemic iron overload rather than to heart failure. Kaiser et al have recently shown that the incidence of cardiac arrhythmias does not increase in the iron overload animal model of the gerbil, even when the level of iron overload induces liver cirrhosis. This observation raises additional questions regarding the link between cardiac arrhythmias and systemic iron overload in HH. As a result, we studied the incidence of cardiac arrhythmias in cardiac asymptomatic subjects with HH with C282Y homozygosity, known to be the most common HFE gene mutation to cause HH. We compared these results to those in age- and gender-matched normal volunteers who lacked HFE mutations.
Methods
We recruited 43 patients with HH and 21 age- and gender-matched healthy volunteer control subjects to participate in a National Heart, Lung, and Blood Institute institutional review board-approved protocol (no. 03-H-0282) from September 2003 to August 2005. The subjects were recruited with the assistance of the National Institutes of Health Clinical Center Patient Recruitment and Public Liaison Office according to the office protocol. All subjects provided written informed consent. The eligibility criteria for those with HH included (1) age ≥21 years, (2) New York Heart Association functional class I, (3) HFE genotype showing homozygosity for the C282Y HFE gene mutation, (4) transferrin saturation >60% or serum ferritin >400 μg/L at the original diagnosis, and (5) absence of significant end organ damage secondary to HH. The subjects with HH were categorized into 2 groups. Group A consisted of newly diagnosed subjects who had undergone <3 lifetime phlebotomy treatments. Group B contained those who had undergone standard phlebotomy treatment for ≥6 months and were documented to be in a stable maintenance phase of therapy, achieving a transferrin saturation of <45% and serum ferritin <30 μg/L during the course of therapy. The control subjects’ eligibility criteria included (1) age ≥21 years, (2) New York Heart Association functional class I, (3) absence of C282Y or H63D mutations in the HFE gene, and (4) normal transferrin saturation and serum ferritin levels. Exclusion criteria included a pattern of excessive alcohol use, uncontrolled hypertension, diabetes requiring the use of >1 oral hypoglycemic agent or insulin, tobacco use within the previous 3 months, and the current use of β-adrenergic blockers or calcium channel blockers. Group A subjects were contacted for a 6-month follow-up repeat evaluation. Those with HH were treated according to the current therapeutic phlebotomy guidelines. These subjects with HH were known to have left ventricular systolic and diastolic function similar to that of the control subjects, as previously reported.
A total of 42 subjects with HH (22 in group A and 20 in group B) and 19 normal volunteer control subjects completed Holter ECG ambulatory monitoring. After proper chest wall skin preparation, leads were placed for 3 channel recordings: CM-V 1 , CM-V 3 , and CM-V 5 positions. Recordings were made using Aria Holter monitors (Del Mar Reynolds, Issaquah, Washington) for approximately 48 hours. The recordings were analyzed using the Impresario Symphony Holter Analyzer (Del Mar Reynolds/Spacelabs Healthcare, Issaquah, Washington) and interpreted by 1 of 2 board-certified cardiologists (Y.S., D.R.), who were unaware of the subject groups.
Continuous data are presented as the mean ± SD and supplemented with the associated median and interquartile range for variables of cardiac arrhythmias. When normality was established with the Shapiro-Wilks test, analysis of variance with the Turkey-Kramer Honestly Significant Difference test as a post hoc test was used to compare the mean values among the 3 groups. An unpaired Student’s t test was used to compare the variables between the combined HH group and control group. A chi-square test was used to compare the categorical data between the combined HH group and the control group. A paired Student’s t test was used to compare the parameters before and after phlebotomy treatment in group A. When normality was in question, the Kruskal-Wallis test was used to compare among the 3 groups, and the Wilcoxon rank-sum test was used to compare between the combined HH group and control group.
Results
The parameters of iron overload (i.e., ferritin, transferrin saturation, and serum iron) were significantly elevated in group A compared to the control group ( Table 1 ), indicating significant iron overload in newly diagnosed subjects with HH. The level of transferrin saturation was significantly greater in group B than in the control group. The left ventricular ejection fraction was calculated using the biplane Simpson method in transthoracic echocardiography and was ≥55% in all HH and control subjects (data not shown). The recording time was shortened in 4 cases in group A, 7 cases in group B, and 1 case in the control group because of subject noncompliance, mechanical device failure, and accidental lead removal. In these cases, the test was not repeated. Thus, the recording time was slightly shorter in group B than in group A. In the Holter symptom log, no symptom associated with cardiac arrhythmias was entered for any subject. The incidence of ventricular ectopy and supraventricular ectopy tended to greater in the combined subjects with HH than in the control group; however, these differences did not reach statistical significance ( Table 2 ). The number of total beats and ectopy rate of supraventricular ectopy in group B subjects with HH were significantly greater than those of normal volunteer controls ( Table 2 ). Nonsustained ventricular tachycardia was noted only in the HH groups; however, the frequency was not statistically significant compared with that in the control group. We have previously reported that the myocardial iron level measured with T2* time constant by cardiac magnetic resonance imaging was comparable among these 3 groups. In cases of newly diagnosed subjects with HH (group A) who could be assessed at 6 months of follow up (n = 20, 2 subjects were lost to follow-up), the incidence of cardiac arrhythmias was not significantly reduced ( Table 3 ) after 6 months of intensive phlebotomy therapy, although the iron level did markedly decreased (ferritin 1,189 ± 899 vs 280 ± 464 μg/dl, transferrin saturation 76 ± 18% vs 48 ± 27%, serum iron 191 ± 43 vs 140 ± 74 μg/dl, before and after 6 months of phlebotomy, p <0.01 for all). No sinus node or more than first-degree atrioventricular node block were noted in both subjects with HH and the control subjects ( Table 3 ).
| Variable | Controls (n = 19) | Group A (n = 22) | Group B (n = 20) | HH Group (n = 42) |
|---|---|---|---|---|
| Age (years) | 48 ± 9 | 48 ± 11 | 52 ± 9 | 50 ± 10 |
| Women | 7 (37%) | 6 (27%) | 7 (35%) | 13 (31%) |
| Ferritin (μg/L) ⁎ | 103 ± 78 | 1,164 ± 886 † ‡ | 127 ± 269 | 670 ± 843 † |
| Transferrin saturation (%) | 25 ± 10 | 76 ± 19 † ‡ | 40 ± 21 † | 58 ± 27 † |
| Serum iron (μg/dl) | 85 ± 27 | 189 ± 49 † ‡ | 109 ± 53 | 150 ± 63 † |
| Hemoglobin (g/dl) | 14.1 ± 1.1 | 14.6 ± 1.6 | 14.1 ± 0.9 | 14.4 ± 1.4 |
| Hematocrit (%) ⁎ | 41.6 ± 3.5 | 44.4 ± 4.5 | 42.0 ± 2.9 | 43.3 ± 4.0 |
| Alanine aminotransferase (IU/ml) ⁎ | 27 ± 13 | 51 ± 24 † ‡ | 28 ± 17 | 40 ± 24 |
| Aspartate aminotransferase (IU/ml) ⁎ | 25 ± 26 | 35 ± 10 † ‡ | 26 ± 10 | 31 ± 11 |
| Glucose (mg/dl) | 99 ± 11 | 97 ± 14 | 95 ± 13 | 96 ± 14 |
| Creatinine (mg/dl) | 0.9 ± 0.2 | 0.9 ± 0.1 | 0.9 ± 0.2 | 0.9 ± 0.2 |
⁎ Parameters analyzed using nonparametric approach; normality was not observed.
| Group | Controls (n = 19) | Group A (n = 22) | Group B (n = 20) | HH (n = 42) |
|---|---|---|---|---|
| Age (years) | 48 ± 9 | 48 ± 11 | 52 ± 9 | 50 ± 10 |
| Recording time (min) ⁎ | 2,690 ± 600 | 2,618 ± 561 † | 2,331 ± 711 | 2,481 ± 645 |
| Average heart rate (beats/min) | 75 ± 9 | 78 ± 7 | 75 ± 9 | 77 ± 8 |
| Minimum heart rate (beats/min) | 52 ± 6 | 51 ± 7 | 50 ± 8 | 51 ± 8 |
| Maximum heart rate (beats/min) | 138 ± 20 | 139 ± 18 | 129 ± 14 | 134 ± 17 |
| Ventricular ectopy | ||||
| Total beats ⁎ | ||||
| Mean ± SD | 20 ± 49 | 284 ± 814 | 39 ± 80 | 167 ± 598 |
| Median, interquartile range | 1,5 | 2,35 | 4,16 | 3,24 |
| Ectopy rate (beats/hour) ⁎ | ||||
| Mean ± SD | 0.41 ± 1.02 | 5.93 ± 16.92 | 0.83 ± 1.70 | 3.50 ± 12.43 |
| Median, interquartile range | 0.02,0.70 | 0.05,0.85 | 0.09,0.32 | 0.08,0.50 |
| Single ⁎ | ||||
| Mean ± SD | 20 ± 49 | 281 ± 813 | 38 ± 80 | 166 ± 597 |
| Median, interquartile range | 1,5 | 2,35 | 2,17 | 2,24 |
| Nonsustained ventricular tachycardia | 0 | 1 | 1 | 2 |
| Sustained ventricular tachycardia | 0 | 0 | 0 | 0 |
| Supraventricular ectopy | ||||
| Total beats ⁎ | ||||
| Mean ± SD | 70 ± 174 | 50 ± 95 | 415 ± 1,248 ‡ § | 224 ± 872 |
| Median, interquartile range | 11,36 | 7,50 | 44,76 | 19,72 |
| Ectopy rate (beats/hour) ⁎ | ||||
| Mean ± SD | 1.45 ± 3.48 | 1.06 ± 1.97 | 11.11 ± 29.93 ‡ § | 5.85 ± 21.05 |
| Median, interquartile range | 0.23,0.70 | 0.15,1.05 | 0.96,2.01 | 0.49,1.69 |
| Single ⁎ | ||||
| Mean ± SD | 73 ± 171 | 44 ± 90 | 140 ± 432 | 90 ± 305 |
| Median, interquartile range | 10,28 | 7,47 | 36,61 | 13,59 |
| Nonsustained supraventricular tachycardia | 3 | 3 | 6 | 9 |
| Sustained supraventricular tachycardia | 0 | 0 | 0 | 0 |
| Sinus node block | 0 | 0 | 0 | 0 |
| First-degree atrioventricular block | 0 | 1 | 2 | 3 |
| More than first-degree atrioventricular block | 0 | 0 | 0 | 0 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
